Project 3: LRRK2 Biology in Parkinson's Disease Parkinson's disease (PD) is a complex neurodegenerative disorder that is both sporadic and familial. It is currently thought that PD results from a combination of environmental factors and genetic susceptibility. Gene mutations in the leucine-rich repeat kinase 2 (LRRK2) have recently been shown to result in autosomal dominant PD. A high prevalence of these mutations in unrelated PD patients strongly suggests that mutant LRRK2 may play a key role in sporadic PD as well. The clinical and pathological phenotypes of LRRK2 PD patients are similar to classic late-onset PD, further emphasizing the potential importance of this gene. Biochemical evidence suggests that aberrant GTPase and kinase activities are linked to disease causing mutations, and may be at the basis of neuronal toxicity and pathogenesis of PD. The cell biology and pathobiological actions of LRRK2 are not yet known. To understand the role of LRRK2 in the function and dysfunction of neurons we have generated LRRK2 knockout mice and LRRK2 transgenic mice. With Cores B, C and D, we will study the neurochemical, neuroanatomical and behavioral changes in these mice as they age. We will explore the effects of oxidative stress in genetically engineered LRRK2 mice to examine the interplay of genetics and environmental effects on neuropathology. Since increased activity of LRRK2 is associated with neurotoxicity we will explore the cellular regulation of LRRK2 expression by the E3 ubiquitin ligase CHIP and its effects on neuronal viability. We expect that LRRK2 functions in large protein complexes and thus we propose to identify and characterize LRRK2 interacting proteins. The goals of this project are to identify and characterize the interaction of LRRK2 and its protein targets with the hope that these studies of LRRK2 may potentially lead to the development of novel therapeutic strategies for the treatment of PD. RELEVANCE (See instructions): Gene mutations in LRRK2 are a common cause of familial and perhaps sporadic PD, yet little is know about how this protein functions, what cellular signaling networks it plays a role in and how mutations cause PD. The goals of this project are to understand the biology of LRRK2 to learn about the pathogenesis familial and sporadic PD and to identify potential new targets for future drug development to treat PD.